Cascade-amplified self-immolative polymeric prodrug for cancer therapy by disrupting redox homeostasis.

The amplification of reactive oxygen species (ROS) generation and glutathione (GSH) depletion in cancer cells represents a promising strategy to disrupt redox homeostasis for cancer therapy. Quinone methide and its analogs (QM) have recently been recognized as potential GSH scavengers for anticancer applications; however, an effective QM prodrug is yet to be developed. In this study, we prepare a self-immolative polymeric prodrug (SPP), which could be selectively degraded to generate large quantities of QMs in cancer cells during the spontaneous stepwise head-to-tail degradation of SPP. The amphiphilic SPP is self-assembled into nano-sized micelles, allowing for encapsulating 2-methoxy-ß-estradiol (2ME), an anticancer drug that produces a large amount of intracellular ROS. When SPP@2ME, as the cascade-amplified prodrug, is treated on the cancer cells, 2ME is rapidly released at the ROS-rich intracellular environment by degradation of SPP, thus generating more ROS that triggers the degradation of more SPP chains. Such a domino-like cascade-amplified feedback loop significantly amplifies oxidative stress and disrupts the redox homeostasis in cancer cells. This unique strategy provides synergistic anticancer therapeutic efficacy and demonstrates an important perception in innovative and precise nanomedicine.

Self-immolative polymer-based immunogenic cell death inducer for regulation of redox homeostasis.

Doxorubicin (DOX), widely used as an anticancer drug, is considered an immunogenic cell death (ICD) inducer that enhances cancer immunotherapy. However, its extended application as an ICD inducer has been limited owing to poor antigenicity and inefficient adjuvanticity. To enhance the immunogenicity of DOX, we prepare a reactive oxygen species (ROS)-responsive self-immolative polymer (R-SIP) that can efficiently destroy redox homeostasis via self-immolation-mediated glutathione depletion in cancer cells. Owing to its amphiphilic nature, R-SIP self-assemble into nano-sized particles under aqueous conditions, and DOX is efficiently encapsulated inside the nanoparticles by a simple dialysis method. Interestingly, when treated with 4T1 cancer cells, DOX-encapsulated R-SIP (DR-SIP) induces the phosphorylation of eukaryotic translation initiation factor 2α and overexpression of ecto-calreticulin, resulting in endoplasmic reticulum-associated ICD. In addition, DR-SIP contributes to the maturation of dendritic cells by promoting the release of damage-associated molecular patterns (DAMPs) from cancer cells. When intravenously administered to tumor-bearing mice, DR-SIP remarkably inhibits tumor growth compared with DOX alone. Overall, DR-SIP may have the potential to elicit an immune response as an ICD inducer.